The generation of cell polarity is crucial for various cellular processes including cell migration, asymmetric division, and neuronal specification. Essentially, cell polarity plays fundamental roles in helping to organize and integrate complex molecular signals in order for cells to make decisions concerning fate, orientation, differentiation, and interaction. In the nervous system, neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which glia form myelin around axons. The formation of myelin is an exquisite example of cell-cell interaction, which consists of the polarized or unidirectional wrapping of multiple layers of membrane concentrically around an axon initiated at the site of the axon-glial interface. While myelination is a highly polarized process, the involvement of cell polarity in its formation remains largely uncharacterized. We have recently identified a novel role for the Par (partitioning defective) polarity complex in the initiation of myelination. This polarity complex localizes asymmetrically in myelin-forming cells at the axon-glial junction, and disruption of Par localization, dramatically inhibits myelination without affecting cell division, migration, or even axonal alignment. We demonstrate that various growth factor receptors and cellular adhesion molecules directly associate with the polarity complex and propose that the Par complex recruits these molecules to the axon-glial junction, polarizing the cell in order to initiate myelination. Our recent findings provide us with a rare opportunity to characterize the presence of this polarized molecular scaffold at the axon-glial junction that leads to the unidirectional activation of myelination. A clear understanding of the molecular and cellular events that pave the way for the myelin- forming cell is vital in advancing therapies for demyelinating diseases such as Multiple Sclerosis, the peripheral neuropathies, and even nerve injury. PUBLIC HEALTH RELEVANCE Neurons and glia share a mutual dependence in establishing a functional relationship that is controlled by the integration of complex molecular signals and pathways. These reciprocal interactions are responsible for multiple processes, including cell survival, proliferation, migration, cell-fate determination, and differentiation. The formation of myelin is an exquisite and dynamic example of cell-cell interaction that involves the myelin- forming cell and the neuron. A clear understanding of the molecular and cellular events that pave the way for the myelin-forming cell is vital in advancing therapies for demyelinating diseases such as Multiple Sclerosis, the peripheral neuropathies, and even after nerve injury.